Functional classification of scaffold proteins and related molecules

In this series of four minireviews the field of scaffold proteins and proteins of similar molecular/cellular functions is overviewed. By binding and bringing into proximity two or more signaling proteins, these proteins direct the flow of information in the cell by activating, coordinating and regulating signaling events in regulatory networks. Here we discuss the categories of scaffolds, anchors, docking proteins and adaptors in some detail, and using many examples we demonstrate that they cover a wide range of functional modes that appear to segregate into three practical categories, simple proteins binding two partners together (adaptors), larger multidomain proteins targeting and regulating more proteins in complex ways (scaffold/anchoring proteins) and proteins specialized to initiate signaling cascades by localizing partners at the cell membrane (docking proteins). It will also be shown, however, that the categories partially overlap and often their names are used interchangeably in the literature. In addition, although not usually considered as scaffolds, several other proteins, such as regulatory proteins with catalytic activity, phosphatase targeting subunits, E3 ubiquitin ligases, ESCRT proteins in endosomal sorting and DNA damage sensors also function by bona fide scaffolding mechanisms. Thus, the field is in a state of continuous advance and expansion, which demands that the classification scheme be regularly updated and, if needed, revised.